Fatty liver disease refers to a lesion with excessive accumulation of fat in liver cells caused by various reasons. Increased fat content in liver cells possibly results from fatty liver disease such as alcoholism, diabetes, hyperlipidemia, excess weight.
Non-alcoholic fatty liver disease (NAFLD) is a clinical pathophysiological syndrome characterized by steatosis of liver cells and lipid accumulation, caused by factors other than alcohols. Its broad spectrum includes pathological phases such as non-alcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH), liver fibrosis, and cirrhosis. The occurrence of this disease is mostly accompanied by increased body weight in patients. With the improvement of the economic level and the change of the life style, the incidence of non-alcoholic fatty liver disease is rising year by year and has become one of the most common chronic liver diseases.
The clinical manifestation of NAFLD varies with the causes, fat content and extent of inflammatory infiltration in liver, disease course, and concomitant underlying diseases such as obesity and diabetes. Most patients (48%-100%) have no symptoms of the liver disease, and a few patients may have nonspecific symptoms such as fatigue, discomfort in the right upper abdomen, or dull pain. Liver enlargement is the only sign in many patients, where the liver function exhibits slight impairment and the transaminase levels are elevated. Currently, it is considered that fatty liver mainly characterized by hepatic fat accumulation is benign, and may be ameliorated by the change of the life style, for example, adjusting the dietary habits and increasing the exercise. Thus, clinical treatment on non-alcoholic fatty liver is rarely reported, and there is no effective drug for clinical use in relieving fatty liver. For inadvertent or inadequate treatment, fatty liver in some patients can progress into irreversible liver diseases such as nonalcoholic steatohepatitis and liver fibrosis, and manifestations such as cirrhosis, jaundice, ascites, and gastrointestinal bleeding may eventually occur. With the occurrence of fatty liver disease, patients often exhibit different degrees of obesity, with a BMI out of limits and a waist-hip ratio out of limits.
Accumulation of liver triglyceride (TG) is reversible, and thus, drug-targeted reduction of TG in liver cells is of significant clinical importance for treatment of fatty liver disease, especially treatment and prevention of further progression of NAFLD.
In view of increased difficulty and high costs in the development of new drugs, the emphasis of drug development has shifted to secondary application of products, for example, expansion of new indications of developed drugs. Since an existing drug has been subjected to clinical trials and clinical observation in many cases for a long time, its safety can be more effectively ensured. Adverse reactions that occur can be appreciated more fully. For developing a new use of a clinical drug, the cost for clinical trials can be relatively reduced. Therefore, the research of a clinical drug to expand its new functions and indications can greatly promote the development of clinical treatment, save health resources, and facilitate the drug to realize its market values.
Zoledronic acid is described as follows: molecular formula: C5H10N2O7P2; chemical name: 1-hydroxy-2-(imidazol-1-yl)-ethylidene-1,1-bisphosphonic acid; zoledronic acid; chemical structure represented by formula I:

At present, zoledronic acid has been widely used clinically for treating metabolic bone diseases such as osteoporosis, osteitis deformans, and cancerous bone metastasis. Zoledronic acid has a significant inhibition effect on bone resorption. Zoledronic acid and also alendronate sodium and risedronate sodium are third-generation bisphosphonate drugs, which are different from first-generation nitrogen-free bisphosphonates such as etidronate sodium and clodronate sodium and second-generation nitrogen-containing bisphosphonates such as pamidronate sodium and tiludronate sodium in that the third-generation bisphosphonate drugs have the strongest bone resorption resistance with less toxic side effects. The primary molecular structure of zoledronic acid comprises a P-C-P group as active group and R1 and R2 groups as pendent substituents. These primary groups determine the biological activity and mechanism of action of zoledronic acid. Clinically, zoledronic acid is mainly targeted to osteoclasts, for example, by blocking bone destruction and resorption by osteoclasts, interfering with the growth of osteoclasts, and inducing the apoptosis of osteoclasts. In addition, zoledronic acid can also be directly targeted to a key enzyme of the mevalonate/isoprenoid pathway in osteoclasts—farnesyl pyrophosphate synthase (FPPS), so that the formation of isoprenoid compounds such as farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) is reduced, and thus several signaling pathways in which GTPases are involved are blocked. However, the use of zoledronic acid in treating fatty liver disease has not been reported.